1009. Gene Therapy for Prostate Cancer by Controlling Adenovirus E1A and E4 Gene Expression with PSES Enhancer

Abstract

PSES is a chimeric enhancer containing enhancer elements from prostate-specific antigen (PSA) and prostate specific membrane antigen (PSMA) genes that are prevalently expressed in androgen-independent (AI) prostate cancers. PSES demonstrates strong activity equivalent to cytomegalovirus (CMV) promoter, specifically in PSA/PSMA-positive prostate cancer cells, the major cell types in prostate cancer in the absence of androgen. We developed a recombinant adenovirus (AdE4PSESE1a) by placing adenoviral E1a and E4 genes under the control of the bi-directional enhancer PSES and enhanced green fluorescent protein (EGFP) gene, for the purpose of intra-tumoral virus tracking, under the control of CMV promoter. Since PSES is very weak in non-prostatic cells, including HEK293 and HER911 that are frequently used to produce recombinant adenovirus, AdE4PSESE1a can only be produced in the HER911E4 cell line which expresses both E1 and E4 genes. AdE4PSESE1a demonstrated similar viral replication and tumor cell killing activity to wild-type adenovirus in PSA/PSMA-positive prostate cancer cells. The viral replication and tumor cell killing activities were dramatically attenuated in PSA/PSMA-negative cells. To test whether AdE4PSESE1a could be used to target prostate tumors in vivo, CWR22rv subcutaneous tumors were induced in nude mice and treated with AdE4PSESE1a via intra-tumoral and tail vein injection. Compared to tumors treated with control virus, the growth of CWR22rv tumors was dramatically inhibited by AdE4PSESE1a via tail vein injection or intra-tumoral injection. These data demonstrate that adenoviral replication can be tightly controlled in a novel fashion by controlling adenoviral E1a and E4 genes simultaneously with a single enhancer.